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Control of Side Effects of Anticonvulsant Drugs
Control of Side Effects of Anticonvulsant Drugs ROBERT S. SCHWAB, M.D. * WILLIAM H. TIMBERLAKE, M.D. ** JOHN A. ABBOTT, M.D.t
usual side effects or unpleasant reactions of anticonvulsant:drugs used in the treatment of epilepsy are classified into 2 main groups: the benign and completely reversible side effects which are in no sense a danger to the patient's life, and the more serious ones which if not recognized promptly may cause death. The ideal anticonvulsant would be one that carries no side~reactions in its use and is effective in preventing all types of convulsions. Unfortunately, no such compound exists today; and since there are a number of different types of epilepsy and combinations of different kinds of seizures in most patients, it is usually necessary to prescribe two or more different drugs in order to achieve a satisfactory control of the spells. ,Another critical variable in the control of seizures is the fact that each ~Jlatient demands exact and painstaking individual regulation of the iI.ri,osage to suit his particular case. When both of these considerations are ~arefully observed by the physician, it is possible to control in a most ;':satisfactory manner the seizures of nearly 85 per cent of the patients 'who THE
* Assistant Clinical Professor of Neurology , Harvard Medical School; Neurologist and Director of Brain Wave Laboratory , Massachusetts General Hospital, Boston. ** Assistant in Neurology, Harvard Medical School and Massachusetts General Hospital. t Instructor in Neurology, Harvard Medical School; Assistant Neurologist, Massachusetts General Hospital, Assistant Di'rector of Brain Wave Laboratory, Massachusetts General Hospital. A portion of this material was shown as an exhibit at the American Medical Association meeting in New York, June 1-5, 1953 and since it was given an award of honorable mention, was shown by request a second time at the interim session, Section on Diseases of the Nervous System, December 1-4, 1953, St. Louis, Missouri. This work was supported by a grant-in-aid from the Sandoz Company, New York.
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R. S. Schwab, W. H. 1 irnberlake, J. A. Abbott 1
have epilepsy. By satisfactory control is meant the complete absence of seizures or their reduction to a few spells in each year. BENIGN SIDE EFFECTS
It must be realized that all drugs have some side effects. '"The side effects are less in the healthier, the heavier and the more energetic patients. They increase the larger the dose of anticonvulsant per kilogram of body weight. For example, a dose of 100 to 200 mg. of phenobarbital in an adult of 150 pounds will usually produce no side effects. However, if the dose is gradually increased side effects eventually will appear, and consist of drowsiness, yawning and slowness in both responses and movement, with dullness of thought. As the drug accumulates in larger amounts in the body, ataxia and nystagmus appear, all clinically typical of barbiturate intoxication. In some parts of the world it is felt that phenobarbital is the safest and, if pushed to high enough doses, the most effective anticonvulsant. When it is used in this way, however, it is inevitable that in perhaps half of the patients taking it toxic levels will be reached before the convulsions are controlled. In our clinic-and this is the pattern in most other places specializing in the treatment of epilepsy-the drug is not pushed to such levels. It is usually combined with other medicines which achieve the control of the seizures that the phenobarbital does not accomplish alone. In these situations the incidence of side effects from phenobarbital is very low; in our group, only 5 per cent. This principle of side effect production applies to practically any drug if used alone. Instead of a single drug it is better to use several different drugs after a careful period of trial and to avoid, if possible, the annoyance and discomfort of any side effect whatsoever. Side effects are increased by the presence of other drugs, fever, toxins or such body burdens as pregnancy. Although sensitivity to anticonvulsants is not related to allergy in general, it is related to previous drug skin reactions. Many of the benign reactions to anticonvulsants (Table 1) disappear with habituation; thus the slight drowsiness caused by Mebaral is usually present only in the first 2 weeks of treatment. Some of these early side effects may be eliminated entirely if the initial doses are less than average, and increments in dosage are made only after the lapse of 5 to 10 days. For example, if the new drug Mysoline is used, about one-third of the patients require some 2 to 3 vveeks before they can tolerate as much as 250 mg. twice a day. In this particular instance initial dosage should be ~ tablet (125 mg.), increased by 72 tablet about every 5 days until a satisfactory seizure control is reached. Unless habituation to a drug is allowed to develop normally, useful drugs will be prematurely condemned and discontinued. Sometimes early benign side effects do not disappear with the development of tolerance. They can often be counteracted by the administration
Control of ASide Effects of Anticonvulsant Drugs
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of other medicines. For instance, amphetamine sulfate 5 mg. twice a day or even three times a day may take care of this situation. A disturbing side effect of some anticonvulsives when first taken is anorexia or epigastric discomfort. Both Dilantin and Mysoline, when taken on an empty stomach, can produce this symptom in some individuals. It usually does not appear if the medicine is taken after meals or after the ingestion of a glass of milk or other snack. Dilantin is available in an enteric coated capsule which will not upset the stomach. Avoidance of an upset stomach is most important in children, if the youngsters are expected to continue taking the medicine. A benign side effect produced by Dilantin, namely benign hypertrophy of the gums, has long been grounds for criticism of this compound. Sometimes this hypertrophy becomes noticeable only when the dose is increased 1 capsule too much per day and will disappear if the total dose is reduced. In other situations where it is preferable to have the gum hypertrophy rather than risk return of seizures, the situation can be kept under control by monthly visits to the dentist, who can painlessly scrape away Table I IlENIGN SIDE EFFECTS
Drowsiness Gum hypertrophy Photophobia Gastritis Mild loss of appetite
Irritability Slight forgetfulness Mild depression Slight slowness of movements Slight loss of skill
Nystagmus Dysarthria Slight ataxia Headache Temporary skin rash
the excess gum tissue. In the interval, vigorous gum massage three times a day will keep the hypertrophy under limited control. Now and then one encounters a benign side effect for which there is no effective method of prevention and which must be accepted as a lesser evil than the spells. Such an example is the reduction or suppression of sexual power by drugs such as Mesantoin and Mysoline, and occasionally phenobarbital and Mebaral. More rarely amphetamine sulfate has been implicated in such situations. In some patients a shift from one effective anticonvulsant to another may correct the condition, as in Case V, below. Other benign side effects such as irritability, slowness of movements or minor loss of skill usually disappear after ~everal weeks or months and do not require specific measures to counteract them. A number of drugs produce mild skin reactiop.s that appear after several weeks in some patients and in a lesser number after only a few days. These are characterized by an itching, papular rash over the stomach, chest and shoulders. They are more common in children than in adults. Sometimes they are severe enough to make the patient desperately uncomfortable for a day or so. In these cases the drug has to be discontinued promptly and another one £ubstituted. It is usual for skin sensitivity to persi~t, although in a few patients a second attempt at
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R. S. Schwab, W. H. Timberlake, J. A. Abbott
treatment using the same drug, particularly if the dosage is reduced and the increments are small, results in no skin rash.! Most clinicians, however, do not favor a second trial of an anticonvulsant drug that has already produced a skin rash. In this connection, one must be certain that the skin rash of the patient is due to the anticonvulsant drug. Occasionally a patient who has been doing well on an anticonvulsant develops a skin infection or a rash from poison ivy, or from another drug that he is taking, and the anticonvulsant drug is falsely blamed and is withdrawn unnecessarily, with a return of the seizures. Phenobarbital occasionally produces skin reactions; Dilantin, rarely. The development or the history of a skin reaction to a drug should always alert the clinician to be unusually careful if the so-called "risk" drugs are to be used. We have analyzed the benign side effects in 200 of our epileptic cases including both private and clinic patients. In the total group no side effects were encountered in 56 per cent. In 36 per cent, one drug produced benign side effects; and in 17 per cent 2 drugs were responsible for side effects. The most benign drug in our series is phenobarbital with side effects in only 5 per cent of the cases. The following drugs produced benign side effects as follows: Milontin, 18 per cent; Tridione and Dilantin, each 23 per cent; Mysoline and Mesantoin, each 36 per cent. Approximately 50 per cent of the side effects mentioned above tend to disappear with habituation or slight reduction of the medication, or by the addition of other drugs, such as amphetamine. The other 50 per cent do not disappear and require either acceptance of the side effect or a change to another anticonvulsant drug. 2 SERIOUS SIDE EFFECTS
Various medical journals throughout the world, even as late as 1953, have reported fatalities following the use of the so-called "risk" anticonvulsants (Tridione, Paradione, Mesantoin, Phenurone). A majority of such tragedies could be eliminated if very strict and conscientious preventive measures were followed. A patient who would be free of his seizures and safe on a certain drug, provided he followed a regimen of strict supervision and caution, should not be denied this calculated risk when circumstances are clear to both patient and physician. Each report of a serious, preventable accident with a useful new drug increases the chance of its being withdrawn or condemned, thus depriving some patients of its benefits. Moreover, it generally discredits therapeutic development and progress. It spreads an unjustifiable fog of conservative pessimism about epilepsy and its treatment to both laity and profession. The paper by Abbott and Schwab3 in 1950 covered the literature up to that time, and analyzed in considerable detail the various kinds of fatal cases encountered in the use of Tridione, Paradione, Mesantoin and Phenurone. Since then we have continued to follow patients in both our clinic and private offices who are on various anticonvulsants including the above mentioned drugs and also the usual preparations which are
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free of these risks. We have had considerable experience with a fifth drug called Thiantoin but we are not reporting data about that drug at this time because it has been withdrawn from the market. (See Table 2). On reviewing the clinical reports (Table 3), it is interesting that the percentages of reversible skin reactions and mild blood disturbances have been about the same (5 to 10 per cent) with all 4 medicines and the Table 2 SERIOUS SIDE EFFECTS
Blood Leukopenia Granulocytopenia Thrombocytopenia Anemia Bleeding tendency-Nose; gums; joints; gastrointestinal tract; uterine purpura Liver Miscellaneous Hepatitis Exfoliative dermatitis Jaundice Nephrosis Acute yellow atrophy Psychotic behavior Severe anorexia Table 3 SUMMARY OF RECENT CLINICAL REPORTS TRIDIONE AND PARADIONE
6 Groups of Cases TOTAL:
375
MESANTOIN
'1 Groups of Cases TOTAL:
600
Reversible skin reactions in 5 to 8 per cent
Reversible skin reactions in 5 to 10 per cent
Mild blood disturbances in 5 to 10 per cent
Mild blood disturbances in 5 to 10 per cent
Severe blood disturbances in 2 to 4 per cent
Severe blood disturbances in 2 to 4 per cent
PHENl1RONE
'1 Groups of Cases TOTAL:
350
Reversible skin reactions in 5 per cent
Liver involvement in 5 per cent
severe blood disturbances have been about half as frequent (2 to 4 per cent). In general the occurrence of a skin rash is a useful warning of impending trouble. General Measures to Prevent Serious Side Eects
1. It is important to have a precise classification and description of the seizures under treatment and this involves careful history from both the patient and his relatives. A complete physical and neurological examination including an electroencephalographic study, if possible, should be done. The importance of doing the above examination is to
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R. S. Schwab, W. H. Timberlake, J. A. Abbott
eliminate the incorrect use of the "risk" drugs as Tridione to treat brief grand mal seizures mistakenly identified as petit mal. 2. One should start with the safest drug or combination of drugs. When it becomes necessary to use one of the "risk" drugs, only one should be used at a time. 3. Small dose increases should be used and one should be sure that auxiliary treatment is al\vays appropriate. The treatment goal should be set at a reasonable compromise. 4. The follow-up examinations must be frequent and adequate. The patient should be informed of the side effects. lIe should understand the treatment plan, the risks, and the follow-up requirements. The patient and his relatives should be encouraged to report side effects. The patient should report to the physician at the first sign of them. 5. Patient should report immediately to physician at first sign of: Skin rash Swollen or sore neck, groin or axilla Spontaneous bleeding Marked loss of appetite-nausea or vomiting Sallow or yellow skin, dark urine, or clay colored stools Weight loss Headache or any other persistent symptoms 6. Physician should obtain the following laboratory data: Hemoglobin, white blood count and differential with estimate of number of polymorphonuclear cells and platelets Complete urinalysis including microscopic and, when Phenurone is used, a urobilinogen test, and repeat these at frequent intervals Not only should a hemoglobin and white blood count be done, but also a differential with estimate of number of platelets, for a decrease in polymorphonuclear cells is often masked in the white blood count by a rise in lymphocytes. The urine should be examined for albumin and red blood cells. In the case of Phenurone, the urobilinogen and icterus indices should be obtained. Any indication of seriously abnormal liver or kidney function or blood formation requires immediate hospitalization and further study. All drugs must be stopped. Appropriate measures must be taken to compensate for the malfunctioning organ or system. Specific Measures
Suggested Procedure for Blood Studies When Using Anticonvulsants That May Affect Blood-Forming Organs (Tridione, Paradione, M esantoin). 1. Before using drugs which may suppress blood cells, obtain a satisfactory white count, a differential count and a hemoglobin determination. If the initial white count is below 4000 it would be unwise to start using any anticonvulsant that might produce leukopenia. If the number of
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polymorphonuclear cells is less than 50 per cent of the total number, or if the hemoglobin is below 10 grams, there would be some risk. 2. It is recommended that a check on the white count, differential and hemoglobin be done 1 week after starting on anticonvulsant medication, and a third complete blood examination 2 weeks later. Subsequent counts should be done monthly for the first 12 months and at least four times a year thereafter. 3. If a definite drop in white cells occurs, as a drop from 6000 to 4000 in the total number, or if the percentage of polymorphonuclear cells drops from 60 to 40 per cent, a repeat examination should be done within 24 to 48 hours. If this reduction does not progress, it is called a controlled leukopenia and the drug may be continued under careful watching. If, however, further reduction is encountered, it is wiser to reduce the amount of medication by 50 per cent. Subsequent drop in either total white count or percentage of polymorphonuclears should be followed promptly by complete elimination of the medicine~or alternatively, and perhaps more simply: (a) If 2500 polymorphonuclear cells per cu. mm. are found, make counts at least every 2 weeks. (b) Make counts often enough to eliminate errors, to follow trends and to establish levels. (c) If 1600 polymorphonuclear cells per cu. mm. are found, stop the medicine. 4. When a level of "controlled leukopenia" is encountered, medication may be maintained but the frequency of the blood examination should be doubled. When counts are below 3000 or the percentage of polymorphonuclears is below 2tj per cent, the patient is best handled in the hospital. Very close supervision should be maintained on all patients whose counts are below normal. Any patient who fails to report for his blood examination should be compelled to give up his medication. In the initial adjustment on the drugs that are likely to produce a drop in white cells, it is wise to issue prescriptions that may be refilled only a certain number of times. Be on the alert for clinical warnings of decrease of any blood elements. These are persistent sore throat, fever or bleeding tendency. It is agreed that the kind of supervision outlined in the preceding paragraphs will protect most of the patients with early signs of leukopenia from catastrophe. rrhere are, however, unusual circumstances where a situation develops in an explosive manner; and both patient and physician should be made aware of the possibility of these. 'I'est for Urobilinogenuria. The test for urobilinogen4 is done on a 2-hour afternoon specimen of urine, collected between 1: 00 and 3: 00 P.M.: that is, at 1:00 P.M. the patient voids and rejects the sample, then collects all urine formed from 1 :00 to 3: 00 P.M., emptying the bladder at 3:00 P.M.
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R. S. Schwab, W. H. Timberlake, J. A. Abbott
1. Note volume of the 2-hour specimen. 2. 2.5 cc. of this freshly passed urine, cooled to room temperature, is mixed with 2.5 cc. of a modified Ehrlich's reagent (0.7 gram p-dimethylaminobenzaldehyde; 150 cc. concentrated hydrochloric acid; 100 cc. distilled water). Add immediately 5 cc. of a saturated aqueous solution of sodium acetate. When the reagents are added in this order, there appears a pink to red color which in its intensity is proportionate to the amount of urobilinogen. The reaction is carried out in an Evelyn tube suitable for use in an Evelyn photoelectric colorimeter. * 3. A blank solution is prepared simply by adding the reagents in the same amount but in reverse order to 2.5 cc. of the same sample of urine in another Evelyn tube. When the reagents are added in this reverse order, no color develops. Shake thoroughly while adding sodium acetate to prevent color development when, later, Ehrlich's reagent is added. If the blank solution shows any color, dilute urine 1: 5 with distilled water and set test up again. 4. Set colorimeter with blank at 100. 5. Read unknown using 565 filter without delay. . v~ume CALCULATION. ConcentratIon per 100 cc. read from a curve X 4 X = METHOD:
---wo
Ehrlich units per 2-hour period. The normal range for 2-hour specimen is 0.2 to 0.7 Ehrlich units. (A series of normals done in a laboratory of the Massachusetts General Hospital ranged from 0.2 to 1.2.) This test should be done at least once a month. FIVE EXAMPLES OF BENIGN SIDE EFFECTS CASE I. Gum Hypertrophy. M. K., a 25 year old female secretary, had mild grand mal, generalized type, at night and rare petit mal seizures during the day. These were reasonably controlled on 3 doses of 100 mg. of Dilantin a day since the age of 16. Because of occupational insecurity due to her rare, short spells, . efforts were made to increase her Dilantin to 4 doses a day. At the end of 3 weeks there was considerable increase in gum hypertrophy with some bleeding. This concerned both the patient and her dentist. Her spells were definitely under better control, however. Milontin 500 mg. three times a day was substituted in part for the Dilantin which was reduced now to 100 mg. twice a day. The same degree of improved control was achieved but the condition of the gums subsided over a period of a month. CASE II. Drowsiness. K. E., a 28 year old female music teacher, gave a history of frequent short petit mal seizures since the age of 12, and occasional grand mal around the menstrual period. There was some control of both seizures by Dilantin and phenobarbital. She was started on Milontin January 15, 1953 in doses of 300 mg. five times a day in addition to Dilantin 100 mg. three times a day and Mebaral100 mg. at bedtime. After a week on this medication the patient complained of being sleepy from about 10 A.M. until supper time with considerable uncontrolled yawning. Elimination of the Mebaral had no effect. Seizures were still present. Medication was switched to Tridione 300 mg. three times a day instead of Milontin with prompt disappearance of the drowsiness as well as control of her seizures. CASE III. Irritability and Skin Rash. C. G., a 9 year old school girl, was referred here by her pediatrician for control of petit mal seizures occurring about six times a day during the past 2 years. She was also irritable and had school
* A set of color standards can be used instead of a colorimeter; such a set may be bought from W. H. Taylor, Baltimore, Maryland.
Control of Side Effects of Anticonvulsant Drugs
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difficulties. EEG abnormalities typical of petit mal seizures were found and no other neurological abnormality. Phenobarbital was given, 30 mg. three times a day with meals. There was a prompt reduction of her small seizures but an increase in her irritability and a slowing up of her responses. Five or 6 days after starting on the medication her mother noticed a skin rash on her chest and back while she was bathing. This consisted of a maculopapular, diffuse rash with slight itching. By the next morning it had spread to her arms, legs and neck. When the patient was seen a day later, it had spread further to involve her face, and she complained of itching. Phenobarbital was promptly stopped and Milontin 500 mg. three times a day substituted. There was a prompt reduction in the irritability and drowsiness and a gradual disappearance of the skin rash over a period of approximately 2 weeks. With the disappearance of the skin rash there was a marked improvement in the patient's work in school and even better control of the small seizures, although EEG showed only a slight improvement in the pattern. Patient has continued to do well on this regimen for the past 9 months. CASE IV. Nystagmus, Dysarthria and Ataxia. N. C., a 27 year old housewife, had generalized seizures since the age of 15 that seemed to occur more frequently around her menstrual period. The seizures were partially under control on 3 capsules of Dilantin a day. In an effort to control them around the period, the patient was instructed to take 500 mg. of enteric-coated ammonium chloride tablets with each meal just before and during the menstrual period and to continue the Dilantin as before. Through a misunderstanding she took 3 capsules of Dilantin with each meal and 1 ammonium chloride tablet only. She appeared 6 days later at the clinic with a severe staggering gait and marked intention tremor. Her voice was dysarthric like that of multiple sclerosis and there was nystagmus on both sides. There were no other neurological signs. She was sent home and instructed in the proper arrangement of her medicine and reaseured that in a few days she would recover her normal health. This occurred. Interestingly, there was no gum hypertrophy during this large Dilantin consumption. CASE V. Loss of Sexual Powers. M. K., a 35 year old male night club entertainer, had rare nocturnal seizures of the automatism type (psychomotor spells), and an occasional epigastric aura during his appearances at the night club. His spells went back to a head injury in his middle 20's. They were considerably reduced and the daytime equivalents were eliminated by 100 mg. of Dilantin and 30 mg. of phenobarbital three times a day. Mesantoin 100 mg. three times a day was then substituted, with better control of all seizures. However, the patient noticed after a few months that he was sexually impotent and this disturbed him. After a few weeks he was switched back to Dilantin and phenobarbital with 30 extra mg. of the latter at night. This gave him satisfactory control of his seizures and return of his sexual powers. Six months later he had a recurrence of the epigastric aura so Mysoline was substituted, 250 mg. three times a day, with prompt disappearance of the symptoms. However, again after a period of several weeks, his sexual difficulty recurred and on his own initiative he returned to Dilantin and phenobarbitaL For the past 3 months satisfactory control has been obtained on this regimen.
FIVE EXAMPLES OF SERIOUS SIDE EFFECTS CASE VI. Tridione. T. L. E., a 7 year old girl, had short attacks of paroxysmal automatism: for example, while tying her shoelaces she would continue toying aimlessly with the laces, staring, and not responding. She would have as many as 3 or 4 spells an hour and remissions rarely lasted longer than 2 or 3 days.
R. S. Schwab, W. H. Timberlake, J. A. Abbott
1348
Neurological examination wasnorlnal. The EEG was abnormal with disturbances in the right occiput (waves at 4 per second) as well as a run of paroxyslnal waves at 3 per second during overbreathing. For control of seizures l)ilantin 100 mgnl. three times daily proved unsatisfactory. Tridione 300 lng. three times daily was added. Two and one-half weeks after starting Tridione, her blood count was normal and she was enjoying a marked reduction in the number of seizures. However, 5 weeks later (7}2 weeks after starting Tridione), while her total white count was again normal, the polYlllorphonuclear cells had dropped lllarkedly to 20 per cent or 1700 per cu. mm. Medication was not changed; in counts done 3 and 7 days after this drop, these cells showed a progressive rise. Because of this rise and the marked reduction in the number of seizures, it was decided to continue with Tridione in the reduced amount of 300 mg. once a day. No change was made in the Dilantin. 11000 10000 9000 8000 7000 6000 5000 4000 3000 2000 1000
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Blood counts were to be done once or twice a week. One week later a second drop occurred involving th~s time not only polymorphonuclears (25 per cent or 1497 per cu. mm.) but total white count too, though the total nUlllber of ,vhite cells was still within normallim~ts. At this point, Tridione was stopped completely; counts done 4, 6 and 11 days later showed a continued plateau of low counts; and a count 14 days later showed a marked rise and no further trouble was encountered. (See Fig. 166.) CASE VII. Mesantoin. J. E. C., a 16 year old school girl, began to have gen·eralized seizures 2 years before the first examination, usually in her sleep at night with occasional tongue biting and wetting. Two weeks before the examination she fell and suffered a severe concussion of the brain. Neurological exalnination was not remarkable. Two EEG's were lnildly abnormal without consistently localized or lateralized abnormalities. She was placed on Mesantoin and Dilantin each 0.1 gram four times a day. The advisability of periodic blood counts in patients taking Mesantoin was first recognized after she had been taking it for 5 lnonths. They showed a progressive decline in the number of polymorphonuclear leukocytes per CU.lnm. This decline began at about the tilne at which serious drops of this sort have been reported in other cases. At first it was not reflected in the total white count. It continued to a level of 1600 polymorphonuclears per
Control of Side Effects of Anticonvulsant Drugs
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cu. mm. At this point Mesantoin was stopped, and the polymorphonuclears rose to their initial level, which they have rnaintained since then. CASE VIII. Mysoline with Mebaral. K. M., a 28 year old \voman, had a history of petit mal and generalized seizures since the age of 12. At the age of 25 there was enough evidence that some of the seizures were due to a cerebral scar and its excision was successfully undertaken. A large number of different medications were tried with partial success. In January 1953 she was placed on Mysoline and Mebaral. There was excellent control of the spells but after 6 weeks the routine white count showed a drop to 3000 with only 50 per cent polymorphonuclear cells. Withdrawal of both drugs caused a prompt return to 6000. Resumption of Mysoline alone was followed by no leukocyte suppression, nor was there any change in this blood picture on Dilantin and Mebaral. When Mebaral was again added to the Mysoline the white count dropped quickly to 2000 and returned again to normal when the Mebaral was omitted. In this particular case an unusual sensitivity of the white cells resulted when 2 drugs were used together, neither of which affected the white cell count alone. This unusual sensitivity to rnixed anticonvulsants must be kept in mind as an additional source of dangerous side effects. At no time was there any subjective or objective evidence of difficulty due to these temporary drops in the white count. CASE IX. Phenurone. Mr. X., aged 43, a well developed and nourished workman, had typical epileptic paroxysmal automatisms (psychomotor seizures) for several years. For instance, while at work he would walk off the job or kiss his foreman, with consequent scandal and embarrassment to himself. He also had seizures in his sleep at night. The EEG's (without activation by sleep) and the neurological examination were normal. A great variety of anticonvulsants was tried without success. Phenurone was first tried for about 1 month (October 9 to Nov. 13, 1948) at 0.5 gram three to five times a day with phenobarbital. It was discontinued at the end of this period because of weakness, anorexia, low fever and coated tongue. There was no jaundice or dark urine. The illness was not clearly attributable to Phenurone. About 1 year later (Sept. 17, 1949) a second trial of Phenurone began. The dose was 0.5 gram three times a day with phenobarbital and Dilantin. First test for urinary urobilinogen was done 3 days later and was normal; second and third tests done 17 and 19 days after starting Phenurone were abnormal. On day of third test, the patient was more tired than usual, but the urine was not dark, sclerae not yellow, no gastrointestinal complaints. Phenurone was discontinued. Latel' Iivel' tests were normal. CASE X. Phenurone~Death.Mrs. Z., a 39 year old housewife, had been under treatment for 4 to 5 years for petit mal and grand mal. She began to take Phenurone in August 1952, dosage not known. Episodes of moodiness and depression occurred while she was taking this medication. In January 1953, five months after starting Phenurone, she developed anorexia, nausea, vomiting, weakness and a tremor of the hands. In February 1953, 6>'2' months after starting on Phenurone, she became confused and jaundiced. She was hospitalized far from hom~ and presulllably Phenurone was stopped at this time. She continued severely ill in the hospital for about 1 month and was then flown to our hospital (nearer her home) on March 18, 1953. When admitted she was disoriented, deeply jaundiced, abdomen was distended, liver was enlarged 2 fingerbreadths below the costal margin, urine showed 3 plus bile, blood counts were normal. Van den Bergh was 16.4/.23; e€phalin was 3 plus; cholinesterase was 0.39 units
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R. S. Schwab, W. H. Timberlake, J. A. Abbott
(normal 0.52); temperature rose gradually from 99° F. on admission to 104 degrees terminally. On second hospital day she enjoyed a short period of lucidity then became restless and irrational. She expired on the third hospital day. ' The postmortem examination of the liver showed extensive necrosis varying in severity in different sections. In the areas most severely affected, large portions of the liver lobules were completely necrotic, and very little remaining intact liver parenchyma was noted. There were areas of extensive hemorrhages. The stroma of the liver was collapsed, containing bile ducts and rare cords of liver cells undergoing degeneration, and was infiltrated ,vith round cells and neutrophils. Some evidence of regeneration in the bile ducts was present but not prominent. Where the process was less severe the necrosis began apparently as a centrolobular process extending peripherally toward the portal space. Many liver cells in these lobules were undergoing necrosis and showed loss of nuclei and intense acidophilic staining of the cytoplasm. Some fatty change was noted and plugging of the bile ducts and capillaries by bile pigment.
SUMMARY 1. The usual side effects of anticonvulsants are divided into 2 groups: the benign and serious. The benign occur in approximately 45 per cent of the patients under treatment. The serious side effects involve the skin, the kidneys, the blood and the liver and they occur in 5 to 10 per cent of the cases when "risk" drugs (Tridione, Paradione, Mesantoin and Phenurone) are used. 2. Procedures to prevent both the benign and serious side effects are described, the cardinal rule being always to start treatment with the safest drug. 3. Individual and careful supervision of all patients on the "risk" drugs by frequent blood counts or liver tests is emphasized. 4. Under such planned supervision the incidence of benign or serious side effects can be greatly reduced and in many cases prevented. 5. Illustrative case reports showing the various types of side effects are included.
REFERENCES 1. Kozol, H. L.: Mesantoin in Treatment of Epilepsy. Arch. Neurol. Psychiat. 63: 235-248, 1950. 2. Kaufman, I. C.: Types of Epilepsy and Their Treatment. Dis. Nerv. Syst. 2: 99-106, 1950. 3. Abbott, J. A. and Schwab, R. S.: The Serious Side Effects of the Newer Antiepileptic Drugs: Their Control and Prevention. New England J. Med. 24-2: 943-949, 1950. 4. Watson, C. J., Schwartz, S., Sborov, V. and Bertie, E.: Studies of Urobilinogen. A Simple Method for Quantitative Recording of Ehrlich Reaction as Carried Out with Urine and Faeces. Am. J. Clin. Path. 14-: 605, 1944. 5. Abbott, J. A. and Schwab, R. S.: Mesantoin in the Treatment of Epilepsy: A Study of Its Effect on the Leukocyte Count in Seventy-nine cases. New England J. Med. 250: 197-199, 1954.
Massachusetts General Hospital Fruit Street, Boston 14, Massachusetts
usual side effects or unpleasant reactions of anticonvulsant:drugs used in the treatment of epilepsy are classified into 2 main groups: the benign and completely reversible side effects which are in no sense a danger to the patient's life, and the more serious ones which if not recognized promptly may cause death. The ideal anticonvulsant would be one that carries no side~reactions in its use and is effective in preventing all types of convulsions. Unfortunately, no such compound exists today; and since there are a number of different types of epilepsy and combinations of different kinds of seizures in most patients, it is usually necessary to prescribe two or more different drugs in order to achieve a satisfactory control of the spells. ,Another critical variable in the control of seizures is the fact that each ~Jlatient demands exact and painstaking individual regulation of the iI.ri,osage to suit his particular case. When both of these considerations are ~arefully observed by the physician, it is possible to control in a most ;':satisfactory manner the seizures of nearly 85 per cent of the patients 'who THE
* Assistant Clinical Professor of Neurology , Harvard Medical School; Neurologist and Director of Brain Wave Laboratory , Massachusetts General Hospital, Boston. ** Assistant in Neurology, Harvard Medical School and Massachusetts General Hospital. t Instructor in Neurology, Harvard Medical School; Assistant Neurologist, Massachusetts General Hospital, Assistant Di'rector of Brain Wave Laboratory, Massachusetts General Hospital. A portion of this material was shown as an exhibit at the American Medical Association meeting in New York, June 1-5, 1953 and since it was given an award of honorable mention, was shown by request a second time at the interim session, Section on Diseases of the Nervous System, December 1-4, 1953, St. Louis, Missouri. This work was supported by a grant-in-aid from the Sandoz Company, New York.
1339
1340
R. S. Schwab, W. H. 1 irnberlake, J. A. Abbott 1
have epilepsy. By satisfactory control is meant the complete absence of seizures or their reduction to a few spells in each year. BENIGN SIDE EFFECTS
It must be realized that all drugs have some side effects. '"The side effects are less in the healthier, the heavier and the more energetic patients. They increase the larger the dose of anticonvulsant per kilogram of body weight. For example, a dose of 100 to 200 mg. of phenobarbital in an adult of 150 pounds will usually produce no side effects. However, if the dose is gradually increased side effects eventually will appear, and consist of drowsiness, yawning and slowness in both responses and movement, with dullness of thought. As the drug accumulates in larger amounts in the body, ataxia and nystagmus appear, all clinically typical of barbiturate intoxication. In some parts of the world it is felt that phenobarbital is the safest and, if pushed to high enough doses, the most effective anticonvulsant. When it is used in this way, however, it is inevitable that in perhaps half of the patients taking it toxic levels will be reached before the convulsions are controlled. In our clinic-and this is the pattern in most other places specializing in the treatment of epilepsy-the drug is not pushed to such levels. It is usually combined with other medicines which achieve the control of the seizures that the phenobarbital does not accomplish alone. In these situations the incidence of side effects from phenobarbital is very low; in our group, only 5 per cent. This principle of side effect production applies to practically any drug if used alone. Instead of a single drug it is better to use several different drugs after a careful period of trial and to avoid, if possible, the annoyance and discomfort of any side effect whatsoever. Side effects are increased by the presence of other drugs, fever, toxins or such body burdens as pregnancy. Although sensitivity to anticonvulsants is not related to allergy in general, it is related to previous drug skin reactions. Many of the benign reactions to anticonvulsants (Table 1) disappear with habituation; thus the slight drowsiness caused by Mebaral is usually present only in the first 2 weeks of treatment. Some of these early side effects may be eliminated entirely if the initial doses are less than average, and increments in dosage are made only after the lapse of 5 to 10 days. For example, if the new drug Mysoline is used, about one-third of the patients require some 2 to 3 vveeks before they can tolerate as much as 250 mg. twice a day. In this particular instance initial dosage should be ~ tablet (125 mg.), increased by 72 tablet about every 5 days until a satisfactory seizure control is reached. Unless habituation to a drug is allowed to develop normally, useful drugs will be prematurely condemned and discontinued. Sometimes early benign side effects do not disappear with the development of tolerance. They can often be counteracted by the administration
Control of ASide Effects of Anticonvulsant Drugs
1341
of other medicines. For instance, amphetamine sulfate 5 mg. twice a day or even three times a day may take care of this situation. A disturbing side effect of some anticonvulsives when first taken is anorexia or epigastric discomfort. Both Dilantin and Mysoline, when taken on an empty stomach, can produce this symptom in some individuals. It usually does not appear if the medicine is taken after meals or after the ingestion of a glass of milk or other snack. Dilantin is available in an enteric coated capsule which will not upset the stomach. Avoidance of an upset stomach is most important in children, if the youngsters are expected to continue taking the medicine. A benign side effect produced by Dilantin, namely benign hypertrophy of the gums, has long been grounds for criticism of this compound. Sometimes this hypertrophy becomes noticeable only when the dose is increased 1 capsule too much per day and will disappear if the total dose is reduced. In other situations where it is preferable to have the gum hypertrophy rather than risk return of seizures, the situation can be kept under control by monthly visits to the dentist, who can painlessly scrape away Table I IlENIGN SIDE EFFECTS
Drowsiness Gum hypertrophy Photophobia Gastritis Mild loss of appetite
Irritability Slight forgetfulness Mild depression Slight slowness of movements Slight loss of skill
Nystagmus Dysarthria Slight ataxia Headache Temporary skin rash
the excess gum tissue. In the interval, vigorous gum massage three times a day will keep the hypertrophy under limited control. Now and then one encounters a benign side effect for which there is no effective method of prevention and which must be accepted as a lesser evil than the spells. Such an example is the reduction or suppression of sexual power by drugs such as Mesantoin and Mysoline, and occasionally phenobarbital and Mebaral. More rarely amphetamine sulfate has been implicated in such situations. In some patients a shift from one effective anticonvulsant to another may correct the condition, as in Case V, below. Other benign side effects such as irritability, slowness of movements or minor loss of skill usually disappear after ~everal weeks or months and do not require specific measures to counteract them. A number of drugs produce mild skin reactiop.s that appear after several weeks in some patients and in a lesser number after only a few days. These are characterized by an itching, papular rash over the stomach, chest and shoulders. They are more common in children than in adults. Sometimes they are severe enough to make the patient desperately uncomfortable for a day or so. In these cases the drug has to be discontinued promptly and another one £ubstituted. It is usual for skin sensitivity to persi~t, although in a few patients a second attempt at
134-2
R. S. Schwab, W. H. Timberlake, J. A. Abbott
treatment using the same drug, particularly if the dosage is reduced and the increments are small, results in no skin rash.! Most clinicians, however, do not favor a second trial of an anticonvulsant drug that has already produced a skin rash. In this connection, one must be certain that the skin rash of the patient is due to the anticonvulsant drug. Occasionally a patient who has been doing well on an anticonvulsant develops a skin infection or a rash from poison ivy, or from another drug that he is taking, and the anticonvulsant drug is falsely blamed and is withdrawn unnecessarily, with a return of the seizures. Phenobarbital occasionally produces skin reactions; Dilantin, rarely. The development or the history of a skin reaction to a drug should always alert the clinician to be unusually careful if the so-called "risk" drugs are to be used. We have analyzed the benign side effects in 200 of our epileptic cases including both private and clinic patients. In the total group no side effects were encountered in 56 per cent. In 36 per cent, one drug produced benign side effects; and in 17 per cent 2 drugs were responsible for side effects. The most benign drug in our series is phenobarbital with side effects in only 5 per cent of the cases. The following drugs produced benign side effects as follows: Milontin, 18 per cent; Tridione and Dilantin, each 23 per cent; Mysoline and Mesantoin, each 36 per cent. Approximately 50 per cent of the side effects mentioned above tend to disappear with habituation or slight reduction of the medication, or by the addition of other drugs, such as amphetamine. The other 50 per cent do not disappear and require either acceptance of the side effect or a change to another anticonvulsant drug. 2 SERIOUS SIDE EFFECTS
Various medical journals throughout the world, even as late as 1953, have reported fatalities following the use of the so-called "risk" anticonvulsants (Tridione, Paradione, Mesantoin, Phenurone). A majority of such tragedies could be eliminated if very strict and conscientious preventive measures were followed. A patient who would be free of his seizures and safe on a certain drug, provided he followed a regimen of strict supervision and caution, should not be denied this calculated risk when circumstances are clear to both patient and physician. Each report of a serious, preventable accident with a useful new drug increases the chance of its being withdrawn or condemned, thus depriving some patients of its benefits. Moreover, it generally discredits therapeutic development and progress. It spreads an unjustifiable fog of conservative pessimism about epilepsy and its treatment to both laity and profession. The paper by Abbott and Schwab3 in 1950 covered the literature up to that time, and analyzed in considerable detail the various kinds of fatal cases encountered in the use of Tridione, Paradione, Mesantoin and Phenurone. Since then we have continued to follow patients in both our clinic and private offices who are on various anticonvulsants including the above mentioned drugs and also the usual preparations which are
control of Side Effects of A nticonvulsant Drugs
1343
free of these risks. We have had considerable experience with a fifth drug called Thiantoin but we are not reporting data about that drug at this time because it has been withdrawn from the market. (See Table 2). On reviewing the clinical reports (Table 3), it is interesting that the percentages of reversible skin reactions and mild blood disturbances have been about the same (5 to 10 per cent) with all 4 medicines and the Table 2 SERIOUS SIDE EFFECTS
Blood Leukopenia Granulocytopenia Thrombocytopenia Anemia Bleeding tendency-Nose; gums; joints; gastrointestinal tract; uterine purpura Liver Miscellaneous Hepatitis Exfoliative dermatitis Jaundice Nephrosis Acute yellow atrophy Psychotic behavior Severe anorexia Table 3 SUMMARY OF RECENT CLINICAL REPORTS TRIDIONE AND PARADIONE
6 Groups of Cases TOTAL:
375
MESANTOIN
'1 Groups of Cases TOTAL:
600
Reversible skin reactions in 5 to 8 per cent
Reversible skin reactions in 5 to 10 per cent
Mild blood disturbances in 5 to 10 per cent
Mild blood disturbances in 5 to 10 per cent
Severe blood disturbances in 2 to 4 per cent
Severe blood disturbances in 2 to 4 per cent
PHENl1RONE
'1 Groups of Cases TOTAL:
350
Reversible skin reactions in 5 per cent
Liver involvement in 5 per cent
severe blood disturbances have been about half as frequent (2 to 4 per cent). In general the occurrence of a skin rash is a useful warning of impending trouble. General Measures to Prevent Serious Side Eects
1. It is important to have a precise classification and description of the seizures under treatment and this involves careful history from both the patient and his relatives. A complete physical and neurological examination including an electroencephalographic study, if possible, should be done. The importance of doing the above examination is to
1344
R. S. Schwab, W. H. Timberlake, J. A. Abbott
eliminate the incorrect use of the "risk" drugs as Tridione to treat brief grand mal seizures mistakenly identified as petit mal. 2. One should start with the safest drug or combination of drugs. When it becomes necessary to use one of the "risk" drugs, only one should be used at a time. 3. Small dose increases should be used and one should be sure that auxiliary treatment is al\vays appropriate. The treatment goal should be set at a reasonable compromise. 4. The follow-up examinations must be frequent and adequate. The patient should be informed of the side effects. lIe should understand the treatment plan, the risks, and the follow-up requirements. The patient and his relatives should be encouraged to report side effects. The patient should report to the physician at the first sign of them. 5. Patient should report immediately to physician at first sign of: Skin rash Swollen or sore neck, groin or axilla Spontaneous bleeding Marked loss of appetite-nausea or vomiting Sallow or yellow skin, dark urine, or clay colored stools Weight loss Headache or any other persistent symptoms 6. Physician should obtain the following laboratory data: Hemoglobin, white blood count and differential with estimate of number of polymorphonuclear cells and platelets Complete urinalysis including microscopic and, when Phenurone is used, a urobilinogen test, and repeat these at frequent intervals Not only should a hemoglobin and white blood count be done, but also a differential with estimate of number of platelets, for a decrease in polymorphonuclear cells is often masked in the white blood count by a rise in lymphocytes. The urine should be examined for albumin and red blood cells. In the case of Phenurone, the urobilinogen and icterus indices should be obtained. Any indication of seriously abnormal liver or kidney function or blood formation requires immediate hospitalization and further study. All drugs must be stopped. Appropriate measures must be taken to compensate for the malfunctioning organ or system. Specific Measures
Suggested Procedure for Blood Studies When Using Anticonvulsants That May Affect Blood-Forming Organs (Tridione, Paradione, M esantoin). 1. Before using drugs which may suppress blood cells, obtain a satisfactory white count, a differential count and a hemoglobin determination. If the initial white count is below 4000 it would be unwise to start using any anticonvulsant that might produce leukopenia. If the number of
Control of Side Effects of Anticonvulsant Drugs
1345
polymorphonuclear cells is less than 50 per cent of the total number, or if the hemoglobin is below 10 grams, there would be some risk. 2. It is recommended that a check on the white count, differential and hemoglobin be done 1 week after starting on anticonvulsant medication, and a third complete blood examination 2 weeks later. Subsequent counts should be done monthly for the first 12 months and at least four times a year thereafter. 3. If a definite drop in white cells occurs, as a drop from 6000 to 4000 in the total number, or if the percentage of polymorphonuclear cells drops from 60 to 40 per cent, a repeat examination should be done within 24 to 48 hours. If this reduction does not progress, it is called a controlled leukopenia and the drug may be continued under careful watching. If, however, further reduction is encountered, it is wiser to reduce the amount of medication by 50 per cent. Subsequent drop in either total white count or percentage of polymorphonuclears should be followed promptly by complete elimination of the medicine~or alternatively, and perhaps more simply: (a) If 2500 polymorphonuclear cells per cu. mm. are found, make counts at least every 2 weeks. (b) Make counts often enough to eliminate errors, to follow trends and to establish levels. (c) If 1600 polymorphonuclear cells per cu. mm. are found, stop the medicine. 4. When a level of "controlled leukopenia" is encountered, medication may be maintained but the frequency of the blood examination should be doubled. When counts are below 3000 or the percentage of polymorphonuclears is below 2tj per cent, the patient is best handled in the hospital. Very close supervision should be maintained on all patients whose counts are below normal. Any patient who fails to report for his blood examination should be compelled to give up his medication. In the initial adjustment on the drugs that are likely to produce a drop in white cells, it is wise to issue prescriptions that may be refilled only a certain number of times. Be on the alert for clinical warnings of decrease of any blood elements. These are persistent sore throat, fever or bleeding tendency. It is agreed that the kind of supervision outlined in the preceding paragraphs will protect most of the patients with early signs of leukopenia from catastrophe. rrhere are, however, unusual circumstances where a situation develops in an explosive manner; and both patient and physician should be made aware of the possibility of these. 'I'est for Urobilinogenuria. The test for urobilinogen4 is done on a 2-hour afternoon specimen of urine, collected between 1: 00 and 3: 00 P.M.: that is, at 1:00 P.M. the patient voids and rejects the sample, then collects all urine formed from 1 :00 to 3: 00 P.M., emptying the bladder at 3:00 P.M.
1346
R. S. Schwab, W. H. Timberlake, J. A. Abbott
1. Note volume of the 2-hour specimen. 2. 2.5 cc. of this freshly passed urine, cooled to room temperature, is mixed with 2.5 cc. of a modified Ehrlich's reagent (0.7 gram p-dimethylaminobenzaldehyde; 150 cc. concentrated hydrochloric acid; 100 cc. distilled water). Add immediately 5 cc. of a saturated aqueous solution of sodium acetate. When the reagents are added in this order, there appears a pink to red color which in its intensity is proportionate to the amount of urobilinogen. The reaction is carried out in an Evelyn tube suitable for use in an Evelyn photoelectric colorimeter. * 3. A blank solution is prepared simply by adding the reagents in the same amount but in reverse order to 2.5 cc. of the same sample of urine in another Evelyn tube. When the reagents are added in this reverse order, no color develops. Shake thoroughly while adding sodium acetate to prevent color development when, later, Ehrlich's reagent is added. If the blank solution shows any color, dilute urine 1: 5 with distilled water and set test up again. 4. Set colorimeter with blank at 100. 5. Read unknown using 565 filter without delay. . v~ume CALCULATION. ConcentratIon per 100 cc. read from a curve X 4 X = METHOD:
---wo
Ehrlich units per 2-hour period. The normal range for 2-hour specimen is 0.2 to 0.7 Ehrlich units. (A series of normals done in a laboratory of the Massachusetts General Hospital ranged from 0.2 to 1.2.) This test should be done at least once a month. FIVE EXAMPLES OF BENIGN SIDE EFFECTS CASE I. Gum Hypertrophy. M. K., a 25 year old female secretary, had mild grand mal, generalized type, at night and rare petit mal seizures during the day. These were reasonably controlled on 3 doses of 100 mg. of Dilantin a day since the age of 16. Because of occupational insecurity due to her rare, short spells, . efforts were made to increase her Dilantin to 4 doses a day. At the end of 3 weeks there was considerable increase in gum hypertrophy with some bleeding. This concerned both the patient and her dentist. Her spells were definitely under better control, however. Milontin 500 mg. three times a day was substituted in part for the Dilantin which was reduced now to 100 mg. twice a day. The same degree of improved control was achieved but the condition of the gums subsided over a period of a month. CASE II. Drowsiness. K. E., a 28 year old female music teacher, gave a history of frequent short petit mal seizures since the age of 12, and occasional grand mal around the menstrual period. There was some control of both seizures by Dilantin and phenobarbital. She was started on Milontin January 15, 1953 in doses of 300 mg. five times a day in addition to Dilantin 100 mg. three times a day and Mebaral100 mg. at bedtime. After a week on this medication the patient complained of being sleepy from about 10 A.M. until supper time with considerable uncontrolled yawning. Elimination of the Mebaral had no effect. Seizures were still present. Medication was switched to Tridione 300 mg. three times a day instead of Milontin with prompt disappearance of the drowsiness as well as control of her seizures. CASE III. Irritability and Skin Rash. C. G., a 9 year old school girl, was referred here by her pediatrician for control of petit mal seizures occurring about six times a day during the past 2 years. She was also irritable and had school
* A set of color standards can be used instead of a colorimeter; such a set may be bought from W. H. Taylor, Baltimore, Maryland.
Control of Side Effects of Anticonvulsant Drugs
1347
difficulties. EEG abnormalities typical of petit mal seizures were found and no other neurological abnormality. Phenobarbital was given, 30 mg. three times a day with meals. There was a prompt reduction of her small seizures but an increase in her irritability and a slowing up of her responses. Five or 6 days after starting on the medication her mother noticed a skin rash on her chest and back while she was bathing. This consisted of a maculopapular, diffuse rash with slight itching. By the next morning it had spread to her arms, legs and neck. When the patient was seen a day later, it had spread further to involve her face, and she complained of itching. Phenobarbital was promptly stopped and Milontin 500 mg. three times a day substituted. There was a prompt reduction in the irritability and drowsiness and a gradual disappearance of the skin rash over a period of approximately 2 weeks. With the disappearance of the skin rash there was a marked improvement in the patient's work in school and even better control of the small seizures, although EEG showed only a slight improvement in the pattern. Patient has continued to do well on this regimen for the past 9 months. CASE IV. Nystagmus, Dysarthria and Ataxia. N. C., a 27 year old housewife, had generalized seizures since the age of 15 that seemed to occur more frequently around her menstrual period. The seizures were partially under control on 3 capsules of Dilantin a day. In an effort to control them around the period, the patient was instructed to take 500 mg. of enteric-coated ammonium chloride tablets with each meal just before and during the menstrual period and to continue the Dilantin as before. Through a misunderstanding she took 3 capsules of Dilantin with each meal and 1 ammonium chloride tablet only. She appeared 6 days later at the clinic with a severe staggering gait and marked intention tremor. Her voice was dysarthric like that of multiple sclerosis and there was nystagmus on both sides. There were no other neurological signs. She was sent home and instructed in the proper arrangement of her medicine and reaseured that in a few days she would recover her normal health. This occurred. Interestingly, there was no gum hypertrophy during this large Dilantin consumption. CASE V. Loss of Sexual Powers. M. K., a 35 year old male night club entertainer, had rare nocturnal seizures of the automatism type (psychomotor spells), and an occasional epigastric aura during his appearances at the night club. His spells went back to a head injury in his middle 20's. They were considerably reduced and the daytime equivalents were eliminated by 100 mg. of Dilantin and 30 mg. of phenobarbital three times a day. Mesantoin 100 mg. three times a day was then substituted, with better control of all seizures. However, the patient noticed after a few months that he was sexually impotent and this disturbed him. After a few weeks he was switched back to Dilantin and phenobarbital with 30 extra mg. of the latter at night. This gave him satisfactory control of his seizures and return of his sexual powers. Six months later he had a recurrence of the epigastric aura so Mysoline was substituted, 250 mg. three times a day, with prompt disappearance of the symptoms. However, again after a period of several weeks, his sexual difficulty recurred and on his own initiative he returned to Dilantin and phenobarbitaL For the past 3 months satisfactory control has been obtained on this regimen.
FIVE EXAMPLES OF SERIOUS SIDE EFFECTS CASE VI. Tridione. T. L. E., a 7 year old girl, had short attacks of paroxysmal automatism: for example, while tying her shoelaces she would continue toying aimlessly with the laces, staring, and not responding. She would have as many as 3 or 4 spells an hour and remissions rarely lasted longer than 2 or 3 days.
R. S. Schwab, W. H. Timberlake, J. A. Abbott
1348
Neurological examination wasnorlnal. The EEG was abnormal with disturbances in the right occiput (waves at 4 per second) as well as a run of paroxyslnal waves at 3 per second during overbreathing. For control of seizures l)ilantin 100 mgnl. three times daily proved unsatisfactory. Tridione 300 lng. three times daily was added. Two and one-half weeks after starting Tridione, her blood count was normal and she was enjoying a marked reduction in the number of seizures. However, 5 weeks later (7}2 weeks after starting Tridione), while her total white count was again normal, the polYlllorphonuclear cells had dropped lllarkedly to 20 per cent or 1700 per cu. mm. Medication was not changed; in counts done 3 and 7 days after this drop, these cells showed a progressive rise. Because of this rise and the marked reduction in the number of seizures, it was decided to continue with Tridione in the reduced amount of 300 mg. once a day. No change was made in the Dilantin. 11000 10000 9000 8000 7000 6000 5000 4000 3000 2000 1000
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Blood counts were to be done once or twice a week. One week later a second drop occurred involving th~s time not only polymorphonuclears (25 per cent or 1497 per cu. mm.) but total white count too, though the total nUlllber of ,vhite cells was still within normallim~ts. At this point, Tridione was stopped completely; counts done 4, 6 and 11 days later showed a continued plateau of low counts; and a count 14 days later showed a marked rise and no further trouble was encountered. (See Fig. 166.) CASE VII. Mesantoin. J. E. C., a 16 year old school girl, began to have gen·eralized seizures 2 years before the first examination, usually in her sleep at night with occasional tongue biting and wetting. Two weeks before the examination she fell and suffered a severe concussion of the brain. Neurological exalnination was not remarkable. Two EEG's were lnildly abnormal without consistently localized or lateralized abnormalities. She was placed on Mesantoin and Dilantin each 0.1 gram four times a day. The advisability of periodic blood counts in patients taking Mesantoin was first recognized after she had been taking it for 5 lnonths. They showed a progressive decline in the number of polymorphonuclear leukocytes per CU.lnm. This decline began at about the tilne at which serious drops of this sort have been reported in other cases. At first it was not reflected in the total white count. It continued to a level of 1600 polymorphonuclears per
Control of Side Effects of Anticonvulsant Drugs
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cu. mm. At this point Mesantoin was stopped, and the polymorphonuclears rose to their initial level, which they have rnaintained since then. CASE VIII. Mysoline with Mebaral. K. M., a 28 year old \voman, had a history of petit mal and generalized seizures since the age of 12. At the age of 25 there was enough evidence that some of the seizures were due to a cerebral scar and its excision was successfully undertaken. A large number of different medications were tried with partial success. In January 1953 she was placed on Mysoline and Mebaral. There was excellent control of the spells but after 6 weeks the routine white count showed a drop to 3000 with only 50 per cent polymorphonuclear cells. Withdrawal of both drugs caused a prompt return to 6000. Resumption of Mysoline alone was followed by no leukocyte suppression, nor was there any change in this blood picture on Dilantin and Mebaral. When Mebaral was again added to the Mysoline the white count dropped quickly to 2000 and returned again to normal when the Mebaral was omitted. In this particular case an unusual sensitivity of the white cells resulted when 2 drugs were used together, neither of which affected the white cell count alone. This unusual sensitivity to rnixed anticonvulsants must be kept in mind as an additional source of dangerous side effects. At no time was there any subjective or objective evidence of difficulty due to these temporary drops in the white count. CASE IX. Phenurone. Mr. X., aged 43, a well developed and nourished workman, had typical epileptic paroxysmal automatisms (psychomotor seizures) for several years. For instance, while at work he would walk off the job or kiss his foreman, with consequent scandal and embarrassment to himself. He also had seizures in his sleep at night. The EEG's (without activation by sleep) and the neurological examination were normal. A great variety of anticonvulsants was tried without success. Phenurone was first tried for about 1 month (October 9 to Nov. 13, 1948) at 0.5 gram three to five times a day with phenobarbital. It was discontinued at the end of this period because of weakness, anorexia, low fever and coated tongue. There was no jaundice or dark urine. The illness was not clearly attributable to Phenurone. About 1 year later (Sept. 17, 1949) a second trial of Phenurone began. The dose was 0.5 gram three times a day with phenobarbital and Dilantin. First test for urinary urobilinogen was done 3 days later and was normal; second and third tests done 17 and 19 days after starting Phenurone were abnormal. On day of third test, the patient was more tired than usual, but the urine was not dark, sclerae not yellow, no gastrointestinal complaints. Phenurone was discontinued. Latel' Iivel' tests were normal. CASE X. Phenurone~Death.Mrs. Z., a 39 year old housewife, had been under treatment for 4 to 5 years for petit mal and grand mal. She began to take Phenurone in August 1952, dosage not known. Episodes of moodiness and depression occurred while she was taking this medication. In January 1953, five months after starting Phenurone, she developed anorexia, nausea, vomiting, weakness and a tremor of the hands. In February 1953, 6>'2' months after starting on Phenurone, she became confused and jaundiced. She was hospitalized far from hom~ and presulllably Phenurone was stopped at this time. She continued severely ill in the hospital for about 1 month and was then flown to our hospital (nearer her home) on March 18, 1953. When admitted she was disoriented, deeply jaundiced, abdomen was distended, liver was enlarged 2 fingerbreadths below the costal margin, urine showed 3 plus bile, blood counts were normal. Van den Bergh was 16.4/.23; e€phalin was 3 plus; cholinesterase was 0.39 units
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(normal 0.52); temperature rose gradually from 99° F. on admission to 104 degrees terminally. On second hospital day she enjoyed a short period of lucidity then became restless and irrational. She expired on the third hospital day. ' The postmortem examination of the liver showed extensive necrosis varying in severity in different sections. In the areas most severely affected, large portions of the liver lobules were completely necrotic, and very little remaining intact liver parenchyma was noted. There were areas of extensive hemorrhages. The stroma of the liver was collapsed, containing bile ducts and rare cords of liver cells undergoing degeneration, and was infiltrated ,vith round cells and neutrophils. Some evidence of regeneration in the bile ducts was present but not prominent. Where the process was less severe the necrosis began apparently as a centrolobular process extending peripherally toward the portal space. Many liver cells in these lobules were undergoing necrosis and showed loss of nuclei and intense acidophilic staining of the cytoplasm. Some fatty change was noted and plugging of the bile ducts and capillaries by bile pigment.
SUMMARY 1. The usual side effects of anticonvulsants are divided into 2 groups: the benign and serious. The benign occur in approximately 45 per cent of the patients under treatment. The serious side effects involve the skin, the kidneys, the blood and the liver and they occur in 5 to 10 per cent of the cases when "risk" drugs (Tridione, Paradione, Mesantoin and Phenurone) are used. 2. Procedures to prevent both the benign and serious side effects are described, the cardinal rule being always to start treatment with the safest drug. 3. Individual and careful supervision of all patients on the "risk" drugs by frequent blood counts or liver tests is emphasized. 4. Under such planned supervision the incidence of benign or serious side effects can be greatly reduced and in many cases prevented. 5. Illustrative case reports showing the various types of side effects are included.
REFERENCES 1. Kozol, H. L.: Mesantoin in Treatment of Epilepsy. Arch. Neurol. Psychiat. 63: 235-248, 1950. 2. Kaufman, I. C.: Types of Epilepsy and Their Treatment. Dis. Nerv. Syst. 2: 99-106, 1950. 3. Abbott, J. A. and Schwab, R. S.: The Serious Side Effects of the Newer Antiepileptic Drugs: Their Control and Prevention. New England J. Med. 24-2: 943-949, 1950. 4. Watson, C. J., Schwartz, S., Sborov, V. and Bertie, E.: Studies of Urobilinogen. A Simple Method for Quantitative Recording of Ehrlich Reaction as Carried Out with Urine and Faeces. Am. J. Clin. Path. 14-: 605, 1944. 5. Abbott, J. A. and Schwab, R. S.: Mesantoin in the Treatment of Epilepsy: A Study of Its Effect on the Leukocyte Count in Seventy-nine cases. New England J. Med. 250: 197-199, 1954.
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